How does the study of common perinatal brain insults facilitate knowledge about the principles of post-natal neural development? - Chapter 7

Perinatal brain insults are brain insults that occur between 28 weeks of gestation to 28 days after birth. Common perinatal brain insults, which are discussed in this chapter, are preterm (PT) birth, hypoxic-ischaemic encephalopathy (HIE) and perinatal stroke (PS). These perinatal insults provide a unique opportunity to study the fundamental principles of post-natal neural development. In addition, they facilitate a more nuanced understanding of the dichotomy early plasticity versus greater vulnerability. Current evidence suggests that there are both possibilities and restrictions in the degree to which early brain injury becomes integrated into the ongoing dynamic and adaptive processes of neurodevelopment. 

What are the characteristics of preterm birth?

Epidemiology

Preterm birth (PT) refers to the delivery of a live foetus prior to 37 weeks of completed gestation. PT can be subdivided into late PT (LPT) for deliveries prior to 37 weeks, very PT (VPT) for deliveries prior to 32 weeks, and extremely PT (EPT) for deliveries prior to 28 weeks. Another subdivision can be made according to weight with weight below 2500 grams, 1500 grams, and 1000 grams, considered low birth weight (LBW), very low birth weight (VLBW), and extremely low birth weight (ELBW) respectively. Birth weight and gestation duration are considered to be correlated, but not interchangeable. Classification by gestational age is preferred, because it provides a better predictor of the maturation of the organ systems and other developmentally regulated processes that birth weight does. 

The overall rate of PT birth has increased. Advances in neonatal care, including steroid therapy, ventilator techniques, and surfactant therapy, as well as enhanced nutrition have led to a reduction of mortality, in particular in EPT infants. Despite the overall increase in survival rate, the rates of major disability, including moderate to severe intellectual disability, cerebral palsy, epilepsy, blindness, and sensori-neural deafness, have remained rather constant.

Aetiology

There are multiple causes of preterm birth. Some of these factors relate to maternal well-being and others to factors within the infant. Maternal risk factors include age (below 20 or above 35) and maternal obesity, smoking, illicit drug use, heavy alcohol consumption during pregnancy, malignancy, hypertension, pre-eclampsia, intrauterine infection, and placental disorders. In the infant, foetal abnormalities and IUGR may require medical intervention. A quarter of the PT births is caused by early delivery as a planned medical intervention. The remainder occurs spontaneously, many for unknown reasons. A greater risk for PT rupture of membranes is caused by multiple pregnancies, which occur in two to three per cent of all pregnancies and account for approximately 20% of all PT births. 

Neuropathology

Due to preterm birth, major organ systems are immature, leaving the infant at risk for medical complications including respiratory difficulties, cardiac problems and infections, as well as brain injury. Although all organ systems are immature in PT infants, the brain is particularly vulnerable. PT birth occurs at a crucial time of rapid brain development (brain size increases fourfold in the third trimester of pregnancy and myelinated white matter increases fivefold in this last trimester). PT birth conveys risk for both acquired brain injury and disruption of normal brain development thereafter. Specific forms of brain injury that follow from PT birth include germinal matrix IVH (GM-IVH) which refers to bleeding in the germinal matrix (a transient structure within the developing brain located along the flow of the lateral ventricles), periventricular haemorrhagic infarction (PHI), cystic PVL, diffuse white matter injury, and grey matter abnormalities. Around 15% of PT survivors is affected by spastic cerebral palsy. Other manifested symptoms are seizure disorders, sensory problems including blindness and sensori-neural deafness, impaired motor deficits, and attention and learning problems at school age.

Neuropsychological findings

A range of negative neurodevelopmental outcomes have been documented in PT born children. A large meta-analysis concerning general intelligence revealed a consistent pattern of lower scores in children born PT in comparison to healthy controls. Another study found that 14 to 25% of children born VPT score more than two standard deviations below the mean on IQ tests. In addition, studies have found elevated rates on language delay and language impairment in children born PT, especially those born VPT or EPT. Some researchers have argued that these language difficulties can be explained by global cognitive deficits, while others suggest a more specific impairment affecting both expressive and receptive skills, including phonological processing, grammar, fluency, higher-level comprehension, discourse and pragmatics. Due to the high risk of white matter abnormalities following PT, it is not surprising that information processing skills are affected. Further, a range of attention deficits have been documented, including orientation, shifting, and divided attention, as well as executive control of attentional resources. 

Functional outcomes 

Due to the range of cognitive difficulties described in the previous paragraph, it is not surprising that PT birth has a negative affect on academic achievement. There is a linear relationship between degree of prematurity and academic difficulties. Although some studies found greater difficulty in one domain over the other, a recent review suggests more global difficulties, including poorer performance on standardised tests of reading, mathematics, and writing, as well as a higher rate of repeated grades and need for special educational support. A researcher suggested that the triad of attention, memory, and self-regulatory deficits mostly contribute to the learning difficulties as they compromise the capacity of the child to benefit from educational opportunity. Further, the relationship between non-right-handedness and academic outcomes is stronger in children born PT and appears to be mediated by the integrity of the neonatal corpus callosum. 

PT and subsequent physical separation during hospitalisation pose risks on optimal socio-emotional development of the child. The parent-infant attachment is likely to be affected by parental anxiety about the survival and well-being of their infant. Further, neurological impairment in the infant appears to increase the risk for disorganised or insecure attachment. Other symptoms commonly found are behaviour problems, internalising symptoms, and social difficulties. In addition, an elevated risk for psychiatric disorders is documented, which appears to escalate in adolescence, reflected by increased social isolation, risk aversion, and poorer behavioural self-regulation. A finding specific to the PT population is that of increased attention problems without the presence of comorbid hyperactivity/impulsivity. Moreover, a higher rate of comorbid ASD is documented. 

Despite improvements in medical management, PT birth still is associated with increased stress levels in families and long-term morbidity in the surviving infants. There appears to be an elevated level of anxiety, depression, and post-traumatic stress symptoms in mothers of PT infants. Another study found persistent mental health symptoms in both mothers and fathers at six months after the birth of their PT born child. Persisting parental psychopathology in turn is associated with longer-term outcomes for the PT born child, including poorer neurocognitive and academic outcomes at age seven. Longitudinal studies show little proof of 'catching up' with some studies even pointing towards greater functional deficit over time. 

Treatment

There is a long history of interventions following PT birth. In general, these interventions tended to be heterogeneous in focus and content, which makes it difficult to evaluate their efficacy. The cornerstone of good clinical management appears to be neuropsychological assessment at key time-points along the developmental pathway. Such assessment should comprise global measures of ability as well as documentation of the specific strengths and weaknesses of the child. Parent and teacher observations should form an integral piece of the assessment. Interventions should be targeted to individual needs as well as family circumstances. Further, attentional, sensory, and motor deficits may confound performance, even when the target skill is intact. Therefore, motor-free and untimed tasks should be included in the assessment procedure where possible and caution is required when interpreting the result to avoid drawing spurious conclusions. 

What are the characteristics of hypoxic-ischaemic encephalopathy?

Epidemiology

Neonatal encephalopathy (NE) is an umbrella term used to describe compromised neurological functioning in the human infant in the first days of life. A subgroup hereof is hypoxic-ischaemic encephalopathy (HIE), which refers to infants with NE in the context of perinatal asphyxia without other genetic or metabolic syndromes that might induce clinical signs of neurological functioning. HIE occurs in approximately 1 to 6 of 1,000 births. There is a high rate of mortality in HIE (around 10%). HIE is the major cause of neurodevelopmental disability following full-term birth; approximately half of the survivors of severe HIE have substantial long-term neurodevelopmental disabilities, including cerebral palsy, sensori-neural hearing loss, cortical blindness, epilepsy, and cognitive impairment. Children with moderate HIE form the most heterogeneous group in which there is high variability in outcome. There appears to be a dose-response effect of HIE which leads to a continuum of morbidity in this moderate subgroup, that is not well captured by a discrete classification system. 

Classification

HIE is usually classified according to a system proposed by Gonzales and Miller (2006). First, the grading of encephalopathy is determined using six signs, each of which is scored 0 if normal and 1 if abnormal. The six encephalopathy signs are:

1. Alertness (0 = alert).
2. Tone (0 = normal).
3. Flexes (0 = normal).
4. Respiratory status (0 = normal).
5. Feeding (0 = normal).
6. Seizures (0 = none).

Second, there are three clinical stages of encephalopathy. Each stage has a different profile on:

1. Level of consciousness.
2. Neuromuscular control.
3. Complex reflexes.
4. Autonomic function. 
5. Seizures. 

The first stage is characterised by: hyperalert consciousness, normal neuromuscular control, weak complex reflexes, sympathetic autonomic function, and no seizures. The second stage is characterised by: lethargix or obtunded consciousness, mild hypotonia, weak or absent complex reflexes, parasympathetic autonomic function, and common seizures. The third stage is characterised by stuporous level of consciousness, flaccid neuromuscular control, absent complex reflexes, depressed autonomic function, and uncommon seizures.  

Neuropsychological findings

Language may be more sensitive to HIE-related brain damage than visual processing skills. One study found that speech and hearing in particular are impaired. Mild HIE is associated with no or only minimal academic difficulties, while moderate and severe HIE is associate a high degree of academic difficulties, noted by deficits in specific skills as well as delayed school readiness, and increased need for special educational support. Academic difficulties are global, extending to both literacy and numeracy skills. In addition, behaviour problems have been found, including anxiety, hyperactivity, attention difficulties, and social problems.

Treatment

There is little research documenting psychological interventions tailored to HIE survivors, but there are several medication interventions documented that aim to reduce adverse neurodevelopmental sequelae. Currently, a potential neuroprotective agent, erythropoietin, is being studied in several centers. Yet, evidence of its efficacy in reducing long-term consequences is not yet available. 

What are the characteristics of perinatal stroke?

Epidemiology

Perinatal stroke (PS) refers to conditions where there is focal disruption of cerebral blood flow secondary to a blockage (known as ischaemic stroke), rupture of an artery or vein (known as haemorrhagic stroke, HS) or a cerebral sinovenous thrombosis (CSVT) in the brain during foetal or early post-natal life. The majority (80%) of PS is formed by perinatal arterial ischaemic strokes (PAISs). PAIS is often associated with seizures or other clear signs of acute neurological distress such as lethargy, apnoea, or hypotonia in the early post-natal period. However, delayed diagnosis is common, for instance in the first year of life, when parents note some neurodevelopmental abnormality, typically asymmetrical body movements or seizure activity. PAIS accounts for approximately one quarter of all childhood strokes. Although mortality rates are low (1-3%), morbidity following PS is considerable with approximately 80% of survivors manifesting one or more of the following: cerebral palsy, cognitive impairment, ongoing seizure disorders, and cortical sensory deficits. 

Several maternal, fetal/neonatal, and environmental risk factors have been identified. These are listed below:

• Maternal factors: thrombotic state of pregnancy, thrombophilias (acquired or inherited), drug abuse, pre-eclampsia, infection, infertility, fertility treatment, labor and delivery complications.
• Fetal/neonatal factors: inherited thrombophilias, twin-twin transfusion, infection, perinatal asphyxia, congenital heart disease, hypoglycemia, polyglycemia, cathether-related complications.
• Environmental risk factors: gender, race, dehydration, antiphospolipid antibodies. 

Functional outcomes

PS occurs at a time of dynamic neural organisation. Therefore, there is potential for adaptation and compensatory reorganisation of neural networks. However, functional outcomes are often abnormal and may involve the supposedly intact hemisphere. 

Generally, IQ scores of PS survivors are within the average range, although the scores are lower than those of comparison or normative samples. One important determinant of IQ is age at assessment, with lower scores found in children who were assessed later (after age 7), leading the researchers of that study to suggest that limits of functional plasticity become apparent as the complexity of task demands increase and exceed the processing capacity of an under-resourced brain. Further, approximately half of the survivors of PS exhibit compromised receptive and expressive language skills. Other studies demonstrated deficits in visual pattern analysis and visual memory, particularly in PS survivors with occipito-temporal lesions. 

Treatment

In contrast to previous believes that plasticity in a young brain ensures more favourable outcomes, most studies report poorer outcomes following a perinatal event than after stroke occurring later in adulthood. A recent study described a curvilinear relationship between age of insult and outcome, with children experiencing stroke prior to six months and after six years having the poorest cognitive outcomes. There is not much research and evidence regarding educational and behavioural outcomes in survivors of PS. 

To date, there is little empirical evidence to guide systematic intervention for children with PS. Treatments to minimise spasticity and to maximise function are conventional physiotherapy and occupational therapy as well as botulinum toxin injections and surgical interventions. In addition, neuroprotective treatments such as caspase inhibitors, erythropoietin, and omega-3 polyunsaturated fatty acid supplementation have been proposed to minimise damage to the neonatal brain. While they are attracting growing interest, there is not yet convincing evidence for their efficacy. 

Conclusion

To conclude, the brain functions an as integrated and dynamic system. Early injury of the brain affects only the specific location of injury, but also ensures that (sub)cortical neural networks mature in the context of the damaged brain. Skills that are in development of are yet to be acquired are more vulnerable than previously established skills. Hence, the earlier the insult, the greater the potential for cumulative functional deficit. Since perinatal deficits occur by definition very early in life, they provide a unique opportunity to study the possibilities and the limitations of the brains' capacity to reorganise and adapt following such an early insult. To date, research indicates that both vulnerability and plasticity follow perinatal insult. Plasticity is demonstrated, for example, by the fact that children are not aphasic after PS, and most children function within average limits on standardised measures of IQ. Vulnerability, on the other hand, is demonstrated by the subtle deficits in neuropsychological profiles of survivors of PT birth, HIE, and PS, suggesting that reorganisation, in particular during the critical neurodevelopmental stages, may result in inappropriate neural connections, or 'overcrowding' of brain regions, to which function in transferred following early brain injury.